Mirna Therapeutics, a Texas-based company, is developing non-small cell lung cancer (NSCLC) therapies using tumor suppressor miRNAs. This approach, miRNA replacement therapy, is based on the concept that re-introduction of miRNAs depleted in cancer cells reactivates cellular pathways that drive a therapeutic response. Mirna is developing 5 miRNA candidates and has extensive data showing that therapeutic delivery of miRNAs mimics robustly inhibits tumor growth and is well tolerated in pre-clinical animal studies. In agreement with preliminary data, we hypothesize that miRNAs will sensitize cancer cells to conventional therapies which will generate more efficacious cancer treatments with minimal toxicity in normal tissues. In this proposal, we seek to systematically evaluate the combinatorial effects of miRNA mimics and conventional therapies that are most commonly used in the clinic today. The studies will feature the chemotherapeutic agents cisplatin, carboplatin, gemcitabine and paclitaxel, as well as 5 mimics of the most efficacious tumor suppressors that Mirna has identified over the course of an 8-year research program using cell and animal models of cancer and are now part of its pipeline for therapeutic development. A key strength of this proposal is access to lung cancer cell lines for which sensitivity and resistance to conventional therapies are well documented. In Aim 1, miRNA/chemo combinations will be evaluated using cancer cells that are either sensitive or resistant to the individual chemotherapy to identify those that are more effective than chemo alone. In Aim 2, the 1-2 most effective miRNA/chemo combos will be evaluated in the animal models of cancer. The goal of this proposal is to identify a miRNA/chemo combination with improved efficacy for further clinical development. PUBLIC HEALTH RELEVANCE: Combinatorial therapy is broadly viewed as the most effective way to treat cancer. Using models of lung cancer, this proposal seeks to evaluate the combination of conventional chemotherapies with therapeutic miRNAs, a promising class of anti-cancer agents. The goal is to identify a miRNA/chemo combination that is more effective than chemotherapy alone.